Transition metal complexes that can cleave DNA are widely known as xe2x80x9cchemical nucleases.xe2x80x9d See, e.g., Pyle and Barton (1990) Prog. Inorg. Chem. 38: 413; Sigman et al. (1987) Acc. Chem. Res. 26: 98; and Stubbe and Kozarich (1987) Chem. Rev. 87: 1107. These complexes strongly bind to DNA and then cleave it under various conditions. For example, a transition metal complex can cleave DNA upon linking to a DNA-cleaving motif, e.g., acridine orange (Lippard et al. (1984) J Am. Chem. Soc. 106: 6102); upon X-ray irradiation (Grokhovsky and Zubarev (1991) Nucl. Acids Res. 19: 257); or under photolytic conditions (Rudnicki et al. (1991) Bioorg. Med Chem. Lett. 1: 451; or Thorp et al. (1995) J Am. Chem. Soc. 117:11673).
In addition, the just-described transition metal complexes may possess anticancer activity. See, e.g., Bruhn et al. (1987) Prog. Inorg. Chem. 38: 477; and Sherman and Lippard (1987) Chem. Rev. 87: 1153. For example, cisplatin and carboplatin (i.e., platinum complexes) have been routinely used for treating testicular and ovarian cancers (Christian (1992) Semin. Oncol. 19: 720; and Barnard (1989) J Plat. Met. Rev. 33: 162). In addition, many cisplatin derivatives have been developed as new anticancer reagents with less toxic side effect and reduced resistance. See Reedijk (1996) J Chem. Soc., Chem. Commun. 801; and Hambley (1997) Coord. Chem. Rev. 166: 181.
This invention relates to a transition metal complex useful as a nucleic acid binding or cleaving agent.
In one aspect, this invention features a metal complex of the formula: 
M is Pt, Pd, Ni, Co, or Cu; X (including atoms A1 and A2) is aryl, heteroaryl, cyclyl, or heterocyclyl; Y is halogen, tosylate, mesylate, triflate, pyrophosphate, or carboxylate; each of A1 and A2, independently, is N or C; each of A3 and A4, independently, is N, S, or O, wherein A1, A2, A3, and A4 taken together have one positive charge (a charge carried by one of the four atoms, e.g., N+); and each of R1 and R2, independently, is alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, heteroaryloxyl, alkoxylcarbonyl, aryloxylcarbonyl, or heteroaryloxylcarbonyl.
A subset of the metal complexes encompassed by the formula (I) is featured by that M is Pt. In these compounds, X is pyridinyl, one of A1 and A2 is N; Y is halogen; and each of R1 and R2, independently, is alkyl. One exemplary metal complex of this invention is PtCl(DMSO) [xcex72-C5H4SN(O)]: 
Alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, alkoxyl, aryloxyl, heteroaryloxyl, alkoxylcarbonyl, aryloxylcarbonyl, or heteroaryloxylcarbonyl mentioned above refers to both substituted and unsubstituted moieties. As used herein, alkyl is a straight or branched hydrocarbon chain containing 1 to 6 carbon atoms. The term xe2x80x9csubstitutedxe2x80x9d refers to one or more substituents (which may be the same or different), each in replace of a hydrogen atom. Examples of substituents include, but are not limited to, halogen, hydroxyl, amino, cyano, nitro, C1xcx9cC6 alkyl, C1xcx9cC6 alkenyl, C1xcx9cC6 alkoxyl, aryl, heteroaryl, or heterocyclyl, wherein alkyl, alkenyl, alkoxyl, aryl, heteroaryl and heterocyclyl are optionally substituted with C1xcx9cC6 alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, or nitro. The term xe2x80x9carylxe2x80x9d refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term xe2x80x9cheteroarylxe2x80x9d refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, pyridinyl, carbazolyl, and indolyl.
A salt of a metal complex of formula (I) is also within the scope of this invention. Such a salt, for example, can be formed between a positively charged substituent (e.g., sulfoxide) on the complex and an anion. Examples of an anion include fluoride, chloride, bromide, iodide, sulfate, sulfite, phosphate, acetate, oxalate, and succinate. Likewise, a negatively charged substituent can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
This invention also features a method for binding or cleaving a nucleic acid. The method includes contacting the nucleic acid with one or more metal complexes described above. Cleavage of the nucleic acid can be achieved by UV irradiation of the metal complex-bound nucleic acid. The nucleic acid described herein refers to a purine-containing DNA or RNA. It can be single-stranded, double-stranded, or partially single-stranded and partially double-stranded. In some embodiments, the method of this invention is performed in an aqueous buffer having a pH value which ranges from 5 to 8. A cleavage can be carried out by using UV light having a wavelength greater than 300 nm.
Other features, objects, and advantages of the invention will be apparent from the description and from the claims.